Atherosclortic Cardiovascular Disease (ASCVD) is the most common cause of death in industrial countries. (AJR 150: 1263-1269 (1988)). Peripheral Vascular Disease (PVD) also contributes to the morbidity and mortality rates in these populations. In both diseases, damage is mediated by an occlusive lesion of the involved vessel. This lesion is generically called a thrombus. A thrombus is an aggregate of elements formed on the wall of an involved vessel from constituents of the blood in response to a thrombogenic stimuli. This process of thrombus formation is termed thrombosis. Body tissues distal to the occlusion are deprived of their normal blood flow and its ensuing benefits.
Over the years various medical interventions have been employed to remove or otherwise treat an offending thrombotic lesion. Although the surgical procedure Coronary Artery By-Pass Grafting (CABG) remains the gold standard for treatment of lesions involving the coronary vessels of the heart, less invasive methods have an established role in this treatment.
Percutaneous transluminal angioplasty (PTA), or balloon angioplasty, has proven to be a useful procedure for the treatment of localized atherosclerotic lesions of both coronary and peripheral vessels. (Merck Manual, 15th Ed., pg 559). Simply stated, this technique involves the cannulation of an affected vessel with special catheters. An uninflated balloon portion of the catheter is introduced into the narrowed vessel lumen so that it is juxtapositioned to the lattice-like network of the forming thrombus. Inflation of the balloon portion of the catheter compresses the offending thrombus against the vessel wall thereby restoring lumen patentability.
Vessels of the human body are lined by a smooth surface known as the endothelium. The innermost layer of the endothelium is called the intima. This impervious layer improves vascular bloodflow hemodynamics and shields deeper vessel wall layers from contact with the blood itself. Unfortunately, successful PTA invariably involves some interruption of this lining with a resulting violation of the barrier it provides between the deeper placed smooth muscle cells (SMC) of the vessel wall and the blood itself. Local hemodynamic flow characteristics are also affected.
Although many questions are left unanswered, it is believed that some combination of these two factors leads to a late recurrence of partial vessel occlusion in 35-40% of otherwise successful PTA procedures. Indeed, about one-third of all patients treated with PTA return for a second or third procedure, thus reducing the long term benefits of the procedure. Therefore, a need continues to exist to increase the long term benefit of PTA by preventing or reducing vessel restenosis.
One mechanism of vessel restenosis is SMC hyperplasia. In histologic sequences that resemble tumor growth, the vessel SMCs dedifferentiate from a contractile to a synthetic phenotype, followed by intense proliferation and the production of connective tissue. It has been proposed that one method of combating restenosis might be the administration of various therapeutic agents known to block intimal and smooth muscle hyperplasia. Systemically administered drugs such as anticoagulants, vasodilator, etc. have so far proven ineffective to prevent restenosis. More radical treatment involving agents such as cytostatic drugs or general enzyme blockers may prevent smooth muscle cell proliferation but often these agents are toxic to humans at the levels necessary to effectively block development of the involved pathology. For that reason, the current inventor has proposed local administration of such agents. In particular, cytotoxic antitumor agents are suggested as a means of selectively damaging the hyperplastic SMCs.
Problems remain however in the exact method by which this local administration should be accomplished. Conventional methods of drug therapy, as discussed above, often result in blood levels of the cytotoxic agent that are dangerous for the patient. Another problem of systemic administration is the inevitable fluctuations of serum drug concentrations that it produces. Even with local administration of these agents, one must consider that the normal bloodflow of the vessel will dilute the local concentration of the therapeutic agent by a wash-out effect. The need remains, therefore, to devise a system whereby otherwise toxic therapeutic agents are concentrated and localized within the affected vessel wall segment.